Project Summary (Abstract) Hysterectomy, or the surgical removal of the uterus, is one of the most common surgical procedures performed in women. The majority of these surgeries are completed prior to the average onset of menopause. Research suggests that in pre-menopausal women, the abrupt loss of circulating ovarian hormones resulting from oophorectomy (the surgical removal of the ovaries) can be detrimental to cognitive aging. However, hysterectomy with ovarian conservation does not result in the same drastic loss of ovarian hormones that occurs with oophorectomy. Whether hysterectomy has a unique impact on cognitive aging is currently unknown. Human research has shown that there may be an increased risk of developing dementia in women who have undergone hysterectomy in young adulthood compared to women who retain their reproductive organs. Using a rat model, the proposed research will investigate the short- and long- term effects of several types of surgical menopause on cognition. In Specific Aim 1, I will determine the impact of variations in surgical menopause on the trajectory of brain aging by evaluating subjects on a behavioral battery assessing learning and memory. Preliminary data from our laboratory suggests that surgical menopause variants have unique effects on cognition; however, neurobiological mechanisms underlying these cognitive changes remain elusive. In recent years, changes in serum gonadotropin levels, including increased luteinizing hormone (LH) levels, have been associated with detrimental cognitive effects after menopause. Furthermore, clinical populations with Alzheimer's disease (AD) tend to exhibit increased LH levels compared to age-matched controls. Indeed, some rodent models of aging and AD have shown that downregulation of LH improves cognitive performance, regardless of estrogen levels. LH is thought to activate signaling cascades downstream that are critical to learning and memory. To this end, in conjunction with the behavior outcomes assessed in Specific Aim 1, Specific Aim 2 will evaluate changes in LH levels and LH receptor expression in the brain, as well as subsequent alterations in ERK1/2-CREB signal transduction, following surgical menopause variations. The overarching goal of this grant is to identify a neurobiological mechanism for the cognitive changes seen during aging and menopause. To accomplish this, this proposal combines a battery of behavioral and neurobiological techniques to provide crucial data helping to resolve the complex behavioral effects of surgical menopause and mechanisms underlying variations in surgical menopause on cognitive aging. Understanding the neurocognitive complexities of surgical menopause will elucidate novel and clinically translatable factors, which will serve to improve women's health and well-being throughout their lifespan.